Although individuals with
autism are known to have significant communication problems, the neural
mechanisms responsible for impaired communication are poorly understood.† We are working with an animal model of autism
to identify a potential cause of speech sound discrimination impairments and
quantify the beneficial effects of two common autism therapies: auditory
training and environmental enrichment. A better understanding of these
mechanisms may aid the design of improved behavioral and sensory therapies to
reduce communication impairments in autism.

Background

Children with autism have difficulty communicating
with others.

It is estimated that 1 in 150 people in the United
States is affected by autism (Newschaffer et al.,
2007). Autism is characterized by social impairments, language deficits, and
repetitive behaviors (Rapin, 1997). Detailed
psychophysical studies have shown that autistic individuals are severely impaired
in their ability to process the subtle cues used in everyday communication and
social interactions (Rapin and Dunn, 2003; Siegal and Blades, 2003; Alcantara
et al., 2004).

Abnormal perception of speech sounds appears to
exacerbate the communication and social impairments characteristic of autism.
Recent functional imaging studies have confirmed serious deficits in speech
sound processing in both children and adults with autism (Boddaert
et al., 2004; Bomba and Pang, 2004). Autistic
children exhibit impaired processing of speech sounds, but not tones (Ceponiene et al., 2003; Kuhl et al., 2005; OramCardy et al., 2005;
Whitehouse and Bishop, 2008). These impairments likely arise from a degraded
neural representation of speech sounds. Less activation is seen in the left
hemisphere in autism in response to speech sounds (Boddaert
et al., 2003), and this hemisphere is thought to be important in processing the
rapid temporal information in speech (Hickok and Poeppel,
2000). Speech sound processing impairments do not improve over time, and are
still seen in adults with autism (Buchwald et al., 1992; Bomba
and Pang, 2004; Gervais et al., 2004). Unfortunately,
the poor spatial and temporal resolution of current imaging methods obscures
the neural basis of the impairment. A better understanding of the neural
representation of speech sounds in autism would be useful in developing more
effective interventions to improve speech and language development.

Although genetic and
epidemiological studies have demonstrated that autism does not have a single
cause, inappropriate regulation of neural plasticity appears to be a major
contributor to each of the diagnostic behavioral deficits. Mutations in a wide
range of genes predispose children to autism, especially genes associated with
synaptic plasticity and arousal mechanisms. Genetic studies have revealed that
mutations in genes associated with neural specification, growth cone guidance,
synapse formation, neuromodulator release or cell signaling can predispose
children to autism (Cook, 2001).

Valproic acid (VPA) is an anticonvulsant and
mood-stabilizer used to treat epilepsy, migraine, and bipolar disease under the
trade names Depakote and Stavzor.† Prenatal exposure to VPA greatly increases
the likelihood of developmental delays (Ardinger et
al., 1988; Moore et al., 2000; Viinikainen et al.,
2006).† Many of these children require
speech therapy or educational support (Moore et al., 2000; Viinikainen
et al., 2006).†† Prenatal exposure to VPA
is also strongly associated with autism (Christianson et al., 1994; Williams et
al., 2001; Ornoy, 2009). It has been estimated that
approximately 10% of VPA exposed children develop autism, compared to the less
than 1% risk in the general population (Moore et al., 2000; Rasalam
et al., 2005).

Autism
therapies likely work by stimulating neural plasticity, but the evidence is
weak.

Speech training and
enrichment are two widely used therapies to reduce the symptoms of autism (Lovaas, 1987; Kasari et al.,
2008; Pickett et al., 2009).† Both
treatments have been hypothesized to generate beneficial forms of neural
plasticity (Burack et al., 2001; Dawson, 2008).
However there is no direct evidence of therapeutic plasticity in autism.†

Recent evidence suggests
that intensive behavioral training can substantially improve language
proficiency in children with language deficits (Merzenich et al., 1996; Tallal et al., 1996; Kujala et
al., 2001; Habib et al., 2002).† More than 300,000 learning-impaired children
have been trained on computer-based games and exposed to modified speech in an
attempt to improve their language ability (Merzenich et al., 1996; Tallal et al., 1996; Tremblay et al., 1998; Kujala et al., 2001; Habib et
al., 2002; McCandliss et al., 2002).† While considerable controversy remains, some
studies have reported improvements as large as two grade levels after three
weeks of training (Merzenich et al., 1996; Tallal et
al., 1996). Anecdotal results indicate computer based speech therapy is also
effective in autistic children (Tallal, 2000).
Although some of these treatments are based on neuroscience research, many of
the most basic questions about the neurological basis of speech comprehension
impairments and rehabilitation remain unanswered (Kraus et al., 1998).†

Both humans and animals
substantially improve their performance on almost any task after several weeks
of practice.† In some cases, the
improvement is specific to the physical features of the training stimuli, and
in other cases improvements generalize to novel stimuli (Fahle,
2005).† Physiological studies in awake
and anesthetized animals have shown that training with simple stimuli can
generate receptive field plasticity that is specific to the region of the
sensory map engaged during training (Buonomano and Merzenich, 1998) (but see
(Brown et al., 2004; Ghose, 2004)).† More recent behavioral studies in rats and
primates have shown that temporal response properties can also be altered by
operant training (Beitel et al., 2003; Bao et al., 2004).†
These results support the general hypothesis that intensive training can
generate cortical plasticity, but these results are insufficient to establish
what forms of plasticity would most benefit speech processing.

Studies of plasticity in
speech impaired subjects typically train on multiple contrasts in hopes of
maximizing the generalization of the training effect.† Eight weeks of training on phonological
awareness, auditory processing, and language processing skills through
interactive games (Earobics, Cognitive Concepts, Inc.,
Evanston, IL) enhanced cortical evoked responses in† children with learning problems
(Diehl, 1999; Hayes et al., 2003).† The
reliability of cortical response timing also increased with training (Warrier et al., 2004).†
Auditory brainstem responses were not altered.† Several months of experience with a cochlear
implant reduces P1 latency in deaf children by 50 to 200 msec
(Sharma et al., 2005).† Collectively,
these results demonstrate the promise of targeted behavioral therapy to
facilitate functional recovery. Understanding the spatiotemporal pattern of
neuronal activity that is evoked by such training may facilitate the design of
new remediation strategies for communication deficits in individuals with
autism (Pickett et al., 2009).†

In research supported by
the Cure Autism Now Foundation, we documented that enrichment improves temporal
response properties in primary auditory cortex (A1).† Specifically, we observed faster onset
latencies and increased paired pulse depression that could serve to improve speech
processing in autism (Engineer et al., 2004; Percaccio et al., 2005).† However, despite the widespread use of
enrichment and speech therapy to treat autism, no human or animal study has
documented the effect of these interventions on neuronal activity induced by
speech sounds.

Our studies will be
conducted in rats because this important model system offers numerous experimental
advantages over other animal models.† The
brain anatomy, physiology, and behavior of rats are the best studied of any
animal species.† More auditory training
studies have been conducted in the rat than in the cat, monkey, and ferret
combined. †The ratís small size and
reasonable cost makes it possible to use a larger number of subjects than would
be possible with many other species.† The
wealth of experimental techniques available and the long history of
neuroscience research on rats suggest this species is a logical choice in which
to investigate the basic neural mechanisms that could contribute to speech
processing impairments in humans.

Scientific Summary

††††††††††† The
poor resolution of human imaging techniques obscures the neural basis of speech
processing impairments, so we propose to evaluate speech sound coding in the valproic acid (VPA) animal model of autism, and quantify
the beneficial effects of two common autism therapies: auditory training and
environmental enrichment. Speech sounds evoke specific spatiotemporal patterns
of cell firing in the central auditory system of normal rats (Engineer
et al. 2008). The first aim of the project is to determine the consequence
of VPA exposure on the collicular and cortical
representations of speech sounds. Our preliminary results indicate that in
utero VPA exposure severely degrades the precise spatiotemporal patterns evoked
by speech sounds in auditory cortex. As in autism, the longer latency in our
animal model is significantly greater for speech sounds compared to tones. The
second aim of the project is to determine the behavioral consequences of VPA
exposure on speech sound discrimination. If the neural spatiotemporal representations
of speech sounds are degraded, then it is possible that certain speech sounds
may not be distinguishable in VPA treated rats. We therefore predict that
speech sound discrimination will be impaired in VPA exposed rats. The third aim
is to determine the effects of speech training and environmental enrichment on
speech evoked activity in VPA exposed rats. Based on previous studies, we
predict that both speech training and environmental enrichment will relieve the
degradation of the cortical responses to speech sounds and restore speech sound
discrimination to control levels in VPA treated rats. The results of the
proposed studies will add to our understanding of the neural mechanisms that
are associated with speech sound coding. Insights derived from these studies
may influence the development of new behavioral and sensory techniques to treat
the communication impairments in autism that result in part from degraded
speech sound discrimination.